The invention relates to electrical stimulation therapy for neurological disorders, and more particularly to a system and method for adapting stimulation waveforms to a measured characteristic of an electrographic signal received from the patient""s brain.
Epilepsy, a neurological disorder characterized by the occurrence of seizures (specifically episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or the perturbation of the autonomic nervous system), is debilitating to a great number of people. It is believed that as many as two to four million Americans may suffer from various forms of epilepsy. Research has found that its prevalence may be even greater worldwide, particularly in less economically developed nations, suggesting that the worldwide figure for epilepsy sufferers may be in excess of one hundred million.
Because epilepsy is characterized by seizures, its sufferers are frequently limited in the kinds of activities they may participate in. Epilepsy can prevent people from driving, working, or otherwise participating in much of what society has to offer. Some epilepsy sufferers have serious seizures so frequently that they are effectively incapacitated.
Furthermore, epilepsy is often progressive and can be associated with degenerative disorders and conditions. Over time, epileptic seizures often become more frequent and more serious, and in particularly severe cases, are likely to lead to deterioration of other brain functions (including cognitive function) as well as physical impairments.
The current state of the art in treating neurological disorders, particularly epilepsy, typically involves drug therapy and surgery. The first approach is usually drug therapy.
A number of drugs are approved and available for treating epilepsy, such as sodium valproate, phenobarbital/primidone, ethosuximide, gabapentin, phenytoin, and carbamazepine, as well as a number of others. Unfortunately, those drugs typically have serious side effects, especially toxicity, and it is extremely important in most cases to maintain a precise therapeutic serum level to avoid breakthrough seizures (if the dosage is too low) or toxic effects (if the dosage is too high). The need for patient discipline is high, especially when a patient""s drug regimen causes unpleasant side effects the patient may wish to avoid.
Moreover, while many patients respond well to drug therapy alone, a significant number (at least 20-30%) do not. For those patients, surgery is presently the best-established and most viable alternative course of treatment.
Currently practiced surgical approaches include radical surgical resection such as hemispherectomy, corticectomy, lobectomy and partial lobectomy, and less-radical lesionectomy, transection, and stereotactic ablation. Besides being less than fully successful, these surgical approaches generally have a high risk of complications, and can often result in damage to eloquent (i.e., functionally important) brain regions and the consequent long-term impairment of various cognitive and other neurological functions. Furthermore, for a variety of reasons, such surgical treatments are contraindicated in a substantial number of patients. And unfortunately, even after radical brain surgery, many epilepsy patients are still not seizure-free
Electrical stimulation is an emerging therapy for treating epilepsy. However, currently approved and available electrical stimulation devices apply continuous electrical stimulation to neural tissue surrounding or near implanted electrodes, and do not perform any detectionxe2x80x94they are not responsive to relevant neurological conditions.
The NeuroCybernetic Prosthesis (NCP) from Cyberonics, for example, applies continuous electrical stimulation to the patient""s vagus nerve. This approach has been found to reduce seizures by about 50% in about 50% of patients. Unfortunately, a much greater reduction in the incidence of seizures is needed to provide clinical benefit. The Activa device from Medtronic is a pectorally implanted continuous deep brain stimulator intended primarily to treat Parkinson""s disease; it has also been tested for epilepsy. In operation, it supplies a continuous electrical pulse stream to a selected deep brain structure where an electrode has been implanted.
Continuous stimulation of deep brain structures for the treatment of epilepsy has not met with consistent success. To be effective in terminating seizures, it is believed that one effective site where stimulation should be performed is near the focus of the epileptogenic region of the brain. The focus is often in the neocortex, where continuous stimulation may cause significant neurological deficit with clinical symptoms including loss of speech, sensory disorders, or involuntary motion. Accordingly, research has been directed toward automatic responsive epilepsy treatment based on a detection of imminent seizure.
The episodic attacks or seizures experienced by a typical epilepsy patient are characterized by periods of abnormal neurological activity. xe2x80x9cEpileptiformxe2x80x9d activity refers to specific neurological activity associated with epilepsy as well as with an epileptic seizure and its precursors; such activity is frequently manifested in electrographic signals in the patient""s brain.
Most prior work on the detection and responsive treatment of seizures via electrical stimulation has focused on analysis of electroencephalogram (EEG) and electrocorticogram (ECoG) waveforms. In general, EEG signals represent aggregate neuronal activity potentials detectable via electrodes applied to a patient""s scalp, and ECoGs use internal electrodes near the surface of or within the brain. ECoG signals, deep-brain counterparts to EEG signals, are detectable via electrodes implanted on the dura mater, under the dura mater, or via depth electrodes (and the like) within the patient""s brain. Unless the context clearly and expressly indicates otherwise, the term xe2x80x9cEEGxe2x80x9d shall be used generically herein to refer to both EEG and ECoG signals.
It is generally preferable to be able to detect and treat a seizure at or near its beginning, or even before it begins. The beginning of a seizure is referred to herein as an xe2x80x9conset.xe2x80x9dHowever, it is important to note that there are two general varieties of seizure onsets. A xe2x80x9cclinical onsetxe2x80x9d represents the beginning of a seizure as manifested through observable clinical symptoms, such as involuntary muscle movements or neurophysiological effects such as lack of responsiveness. An xe2x80x9celectrographic onsetxe2x80x9d refers to the beginning of detectable electrographic activity indicative of a seizure. An electrographic onset will frequently occur before the corresponding clinical onset, enabling intervention before the patient suffers symptoms, but that is not always the case. In addition, there often are perceptible changes in the EEG, or xe2x80x9cprecursors,xe2x80x9d that occur seconds or even minutes before the electrographic onset that can be identified and used to facilitate intervention before electrographic or clinical onsets occur. This capability would be considered seizure prediction, in contrast to the detection of a seizure or its onset.
It has been suggested that it is possible to treat and terminate seizures by applying specific responsive electrical stimulation signals to the brain. See, e.g., U.S. Pat. No. 6,016,449 to Fischell et al., H. R. Wagner, et al., Suppression of cortical epileptiform activity by generalized and localized ECoG desynchronization, Electroencephalogr. Clin. Neurophysiol. 1975; 39(5): 499-506; and R. P. Lesser et al., Brief bursts of pulse stimulation terminate after discharges caused by cortical stimulation, Neurology 1999; 53 (December): 2073-81 . Unlike the continuous stimulation approaches described above, responsive stimulation is intended to be performed only when a seizure (or other undesired neurological event) is occurring or about to occur. This approach is believed to be preferable to continuous or semi-continuous stimulation, as stimulation at inappropriate times and quantities may result in the initiation of seizures, an increased susceptibility to seizures, or other undesired side effects.
While responsive stimulation alone is considered an advantageous therapy for seizures, it is believed possible to further reduce the incidence of seizures by applying continuous or periodic scheduled stimulation to certain parts of the brain while also performing responsive electrical stimulation as described above. See, for example, U.S. patent application Ser. No. 09/543,450 filed on Apr. 5, 2000; U.S. Pat. No. 5,683,422 to Rise; and I. S. Cooper et al., xe2x80x9cEffects of Cerebellar Stimulation on Epilepsy, the EEG and Cerebral Palsy in Man,xe2x80x9dElectroencephalogr. Clin. Neurophysiol. 1978; 34: 349-54.
Some have long recognized that xe2x80x9cseizures may beget more seizuresxe2x80x9d E. H. Reynolds, xe2x80x9cThe Process of Epilepsyxe2x80x9d in T. G. Bolwig et al., ed., The Clinical Relevance of Kindling, ch. 10, p. 149 (Chichester, England: John Wiley and Sons 1989), citing W. R. Gowers, Epilepsy and Other Chronic Convulsive Diseases (London: Churchill 1881 ). Accordingly, an advantage of a device or other treatment that is able to terminate, avoid, or inhibit seizures is that the continued progression of a disease such as otherwise intractable epilepsy may be avoided.
However, there is a need to avoid excess, improper, or regularly repeated stimulation, which may be particularly acute and important in some circumstances, as the central nervous system has a tendency to learn and acclimate to new conditions and stimuli.
As regularly repeated seizures appear to alter the anatomic substrate of the brain (i.e., the neuronal connections, characteristics, and conditions that tend to define the brain""s function), so apparently do xe2x80x9csuitably spaced successive subclinical stimulixe2x80x9d (Reynolds, 1989)xe2x80x94and so might certain predictable and learnable patterns of artificially introduced electrical stimulation that are actually intended to terminate, avoid, or inhibit epileptiform activity. In other words, under certain circumstances, regularly repeated electrical stimulation might eventually result in an increased susceptibility to seizures or other undesired activity, particularly when such stimulation occurs in combination with (or can be associated with) seizures or subclinical activity.
These effects might be attributable to brain mechanisms identical or similar to those involved in learning. See, e.g., E. R. Kandel, xe2x80x9cCellular Mechanisms of Learning and the Biological Basis of Individualityxe2x80x9d in Kandel et al., ed., Principles of Neural Science, 3d ed., ch. 65, pp. 1009-24 (Norwalk, Conn.: Appleton and Lange 1991 ). Relatively short-term and small-scale (neuronal level) learning effects (such as habituation, a form of non-associative learning in which an evoked physiological response decreases continually with repetitive application of the same stimulus) may play a part in this, but there is evidence to support the involvement of more complex long-term memory forming mechanisms, such as long-term potentiation (LTP). Kindling, an experimentally demonstrated effect in which repeated subclinical stimuli eventually cause a laboratory animal""s seizure threshold to decrease, has been postulated to be xe2x80x9cLTP xe2x80x98gone over the topxe2x80x99.xe2x80x9d J. Mellanby and L. Sundstrom, xe2x80x9cKindling, behaviour, and memory,xe2x80x9d in T. G. Bolwig et al., ed., The Clinical Relevance of Kindling, ch. 7, p. 104 (Chichester, England: John Wiley and Sons 1989).
Accordingly, although electrical stimulation intended to terminate epileptiform activity may have enormous clinical benefits for the patient, it is believed possible that using unduly repetitive or predictable stimulation signal patterns may give a patient""s brain the opportunity to learn or acclimate to the patterns, and hence cause the stimulation signal to become less effective over time. Clearly, and consequently, xe2x80x9clearningxe2x80x9d to dismiss or otherwise process therapeutic electrical stimulation may be detrimental to the efficacy of ongoing therapy. It would be beneficial to be able to avoid this effect when possible, and preferable to be able to maintain a high level of neurostimulation effectiveness over time.
Several known neurostimulators tend to provide irregular stimulation signals as a side effect of attempting to use feedback control mechanisms to adapt to sensed electrographic signals. However, these approaches have not met with consistent success.
U.S. Pat. No. 3,850,161 to Liss describes a feedback-controlled system for counteracting brain electrical energy to control epilepsy. The Liss system is the simplest form of feedback-controlled system: it measures an input signal, and if it exceeds a fixed threshold, an inverted version of the input signal is generated as an output.
In U.S. Pat. No. 5,683,422, Rise describes a system for the treatment of neurodegenerative disorders that measures brain activity, and if brain activity is too high, increases the frequency, pulse width, and/or amplitude of a continuous stimulation signal to attempt to block the sensed activity. The Rise patent does not specifically address the treatment of epileptic seizures, and as described above, continuous stimulation can have certain disadvantages when applied near a seizure focus in the neocortex, regardless of signal modulation.
U.S. Pat. No. 5,522,863 to Spano et al. describes a system and method for applying electrical stimulation to disrupt the chaotic behavior of a neural network, i.e. a population of cells in the brainxe2x80x94epileptiform activity is believed by Spano to be chaotic (short-term deterministic yet long-term unpredictable) in nature. The Spano approach may appear to be effective in modifying certain characteristics in vitro, but its applicability in vivo for treating patients is unclear. And in any event, a device that provides the processing power required to establish the existence of a chaotic system in a human patient and to identify stimulation parameters that might disrupt such a chaotic system in real time would be impractical, especially for use in an implantable system.
In U.S. Pat. No. 6,066,163,John describes an xe2x80x9cadaptive brain stimulationxe2x80x9d system and method, primarily intended to induce the recovery of patients in a coma state. The John patent describes a system that is directed to the reinforcement of desired electrographic patterns (to achieve a desired brain state) rather than the disruption of undesired patterns, such as those arising out of an electrographic seizure. Moreover, the John system operates not by reinforcing or modifying the signal pattern directly, but by applying specific treatments, checking for progress (comparing electrographic signals to desired patterns), and following up with treatment accordingly.
Accordingly, it is understood that certain forms of neurostimulation may cause certain behaviors of the nervous system to be learned, and hence might reinforce or tend to induce various desirable or undesirable types of electrographic patterns. As epileptic seizures are frequently characterized by repetitive electrographic patterns, a desirable approach to neurostimulation would tend to disrupt, and not to reinforce or cause to be learned, such electrographic patterns.
Even in the systems described above, which are responsive in various ways to sensed electrographic and other signals, stimulation signal timing generally is not directly correlated to features of the measured electrographic signal, even when the stimulation signal is first started. The parameters frequently varied in such schemes are one or more of frequency, amplitude, phase, and pulse duration for a relatively long stimulation waveform - in most cases continuous or semi-continuous stimulation. Accordingly, while the feedback control provides some level of variability to the stimulation signal, the nature of the stimulation signal is still primarily simple and predictable, particularly in light of existing neural activity. The prevailing theory has been that some signal, and nearly any signal, as long as it is applied in a proper location and with sufficient energy, will distract the brain from its undesired synchronous behavior. 100301
However, the prevailing theory might not be universally true, and in any event, stimulation efficacy appears to vary depending at least in part on phase timing and stimulation signal duration. See, e.g., G. K. Motamedi et al., Abstract (AES 1999), xe2x80x9cBrief Pulse Stimulation Is More Likely To Terminate Afterdischarges During Their Negative Phase, xe2x80x9d Epilepsia 1999; 40(Suppl.7): 136.
To reduce the predictability of a stimulation signal, it may be beneficial to cycle through multiple patterns, or templates, for stimulation waveforms. However, as the human brain is particularly complex and adaptable, it may be able to learn and adapt to even relatively complicated therapy rotation schemes.
Accordingly, and for the reasons set forth above, it is desirable to be able to achieve adaptive and less predictable stimulation signal timing, particularly with regard to stimulation signal phase timing, duration, and amplitude in order to correlate with or intentionally desynchronize EEG activity. Such an adaptive stimulation signal would have adaptive, correlated, or otherwise altered characteristics to attempt to avoid learning, conditioning, habituation, and other similar mechanisms, and may have an increased chance of disrupting epileptiform activity.
In contrast to the known stimulation techniques, the adaptive stimulation system and method of the invention allows a stimulation signal to be adjusted to observed electrographic conditions in real time. This can result in improved results when it is advantageous to stimulate at certain times or with certain stimulation signal parameters to achieve a desired result, when it is desirable to introduce a measure of variability into a stimulation signal to avoid or inhibit undesired learning, conditioning, or habituation, or for both reasons.
A method performed according to the invention for treating a neurological disorder with adaptive stimulation generally begins by detecting an electrographic signal of interest. If the electrographic signal is one for which adaptive stimulation should be applied, the method continues by measuring a characteristic of the electrographic signal, which in a preferred embodiment of the invention is typically a duration or an amplitude of a qualified half wave extracted from the electrographic signal. More than one characteristic can be used. The characteristic is transformed as desired and used to define or modify a stimulation signal, which is then applied preferably at a precise time correlated to a desirable time, which may also be dependent in part on the extracted characteristic.
Accordingly, a system for performing the method described above would generally include an implantable neurostimulator with a detection subsystem, a stimulation subsystem, a central processing unit capable of controlling and coordinating the detection subsystem and the stimulation subsystem, and means of synchronizing stimulation signals to desired events and times.
A system or method according to the present invention is capable of delivering neurostimulation signals that are intentionally altered to provide a measure of variability to stimulation signal timing and other characteristics. This may tend to avoid undesired long-term effects as described above.
Because a neurostimulator according to the invention has multiple detection channels capable of deriving features and characteristics from electrographic signals, no special-purpose circuitry would be necessary to accomplish synchronization, correlation, or alteration according to the invention. In particular, where decorrelation (or pseudo-randomization) is necessary, either a significant quantity of special hardware circuitry or power-intensive software algorithms would typically be necessary to achieve the level of variation desirable to avoid habituation. Accordingly, the approach presented herein is particularly advantageous in that it leverages existing circuitry and algorithms, for example otherwise unused sensing and signal processing channels, to achieve a goal that would otherwise require additional resources.